Cisplatin With or Without Sodium Thiosulfate in Treating Young Patients With Stage I, II, or III Childhood Liver Cancer

Liver Cancer Clinical Trial

— SIOPEL6  

Official title:

A Multi-centre Open-label Randomised Phase III Trial of the Efficacy of Sodium Thiosulphate in Reducing Ototoxicity in Patients Receiving Cisplatin Chemotherapy for Standard Risk Hepatoblastoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00652132
• Other study ID #: RG_09-205
• Secondary ID: CDR0000590649200
• Status: Completed
• Phase: Phase 3
• Start date: December 15, 2007
• Est. completion date: February 28, 2018

Study information

• Verified date: May 2018
• Source: University of Birmingham
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

RATIONALE: Drugs used in chemotherapy, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Chemoprotective drugs, such as sodium thiosulfate, may protect normal cells from the side effects of chemotherapy. It is not yet known whether giving sodium thiosulfate is effective in reducing hearing damage caused by cisplatin in treating young patients with liver cancer.

PURPOSE: This randomized phase III trial is studying how well sodium thiosulfate works to decrease hearing loss caused by cisplatin in treating young patients with stage I, stage II, or stage III childhood liver cancer.

Description:

OBJECTIVES:

Primary

• To assess the efficacy of sodium thiosulfate (STS) to reduce the hearing impairment caused by cisplatin chemotherapy.

Secondary

• To carefully monitor any potential impact of STS on response to cisplatin and survival.

• To assess the short- and long-term tolerability of the combination of STS and cisplatin

• To prospectively evaluate and validate biological, radiological and pathological features of standard-risk hepatoblastoma for future risk adapted management

• To investigate the effect of STS on the formation of cisplatin-DNA adducts.

• To prospectively collect patient DNA specifically for the analysis of possible genetic factors that may contribute to the development of treatment-related ototoxicity and nephrotoxicity

OUTLINE: This is a multicenter study. Patients are stratified according to country, median age (< 15 months vs ≥ 15 months), and PRETEXT tumor classification (I vs II vs III). Patients are randomized to 1 of 2 treatment arms.

• Arm I (Neoadjuvant and adjuvant cisplatin): Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 2 weeks for 4 courses. Patients with progressive disease after course 4 are taken off study. Patients without evidence of disease progression proceed to surgery. Beginning within 3 weeks after surgery, patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 2 weeks for 2 courses in the absence of disease progression or unacceptable toxicity.

• Arm II (Neoadjuvant and adjuvant cisplatin and sodium thiosulphate): Patients receive cisplatin IV over 6 hours and sodium thiosulphate IV over 15 minutes (beginning 6 hours after completion of cisplatin) on day 1. Treatment repeats every 2 weeks for 4 courses. Patients with progressive disease after course 4 are taken off study. Patients without evidence of disease progression proceed to surgery. Beginning within 3 weeks after surgery, patients receive cisplatin IV over 6 hours and sodium thiosulphate IV over 15 minutes (as in neoadjuvant therapy) on day 1. Treatment repeats every 2 weeks for 2 courses in the absence of disease progression or unacceptable toxicity.

Patients undergo blood collection and tumor biopsies periodically for biological and pharmacological studies consisting of biomarker analysis, gene expression profiling, IHC, proteomic analysis, and gene rearrangement analysis. Patients undergo auditory evaluations at baseline, and at the completion of study treatment or at an age of at least 3.5 years to measure ototoxicity and hearing impairment.

After completion of study treatment, patients are followed periodically for at least 5 years.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 116
• Est. completion date: February 28, 2018
• Est. primary completion date: September 4, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Month to 18 Years

Eligibility

Inclusion Histologically confirmed newly diagnosed hepatoblastoma

• Standard risk hepatoblastoma (Pretext I,II,III)

• Age = 18 years and > 1 month

• Written informed consent and national/local ethics committee and regulatory approval

• Centre/country willing and able to organise audiometry at the minimum required quality standard and to provide the contact details of the Consultant Audiologist or Ear Nose and Throat Surgeon who will take the responsibility for seeing that this is done

• Ability to comply with requirements for submission of material for central review

• For females of child-bearing potential, a negative pregnancy test prior to study treatment is required.

• Any patient who is of reproductive age should agree to use adequate contraception for the duration of the trial.

Exclusion:

High risk hepatoblastoma

• Hepatocellular carcinoma

• Treatment starting more than 15 days from written biopsy report

• Abnormal renal function

• Any previous chemotherapy

• Recurrent disease

• Previous hypersensitivity to STS

• Patient unable to follow the protocol for any reason

Related Conditions & MeSH terms

• Hepatoblastoma
• Liver Cancer
• Liver Neoplasms
• Ototoxicity

Intervention

Drug:
• cisplatin

• sodium thiosulfate

Locations

Country	Name	City	State
United Kingdom	Royal Aberdeen Children's Hospital	Aberdeen	Scotland
United Kingdom	Birmingham Children's Hospital	Birmingham	England
United Kingdom	Bristol Royal Hospital for Childre	Bristol	England
United Kingdom	Addenbrooke's Hospital	Cambridge	England
United Kingdom	The Noah's Ark Children's Hospital for Wales	Cardiff
United Kingdom	Royal Hospital For Sick Children	Edinburgh
United Kingdom	Royal Hospital for Sick Children	Glasgow	Scotland
United Kingdom	Leicester Royal Infirmary	Leicester
United Kingdom	Alder Hey Children's Hospital Trust	Liverpool
United Kingdom	Great Ormond Street Hospital for Children	London	England
United Kingdom	Royal Marsden - London	London	England
United Kingdom	Royal Manchester Children's Hospital	Manchester	England
United Kingdom	Queen's Medical Centre	Nottingham	England
United Kingdom	John Radcliffe Hospital	Oxford
United Kingdom	Sheffield Hallam University - City Campus	Sheffield	England
United Kingdom	Southampton Children's Hospital	Southampton

Sponsors (2)

Lead Sponsor	Collaborator
University of Birmingham	Childhood Liver Tumours Strategy Group - SIOPEL

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Rate of Brock grade = 1 hearing loss	To investigate if the administration of sodium thiosulfate simultaneously with the administration of Cisplatin significantly reduces the hearing impairment	End of trial treatment or at an age of 3.5 years, whichever is later
Secondary	Response to preoperative chemotherapy	Defined as: Complete response (CR): no evidence of disease and normal serum AFP value (for age).; Partial response (PR): any tumour volume shrinkage associated with a decreasing serum AFP value, > 1 log below the original measurement.; Stable disease (SD): no tumour volume change and no change, or < 1 log fall of the serum AFP concentration.; Progressive disease (PD): unequivocal increase in 1 or more dimensions and/or any unequivocal increase of the serum AFP concentration (three successive 1-2 weekly determinations) even without clinical (physical and/or radiological) evidence of tumour re-growth.	Following completion of preoperative chemotherapy
Secondary	Complete resection	Total macroscopic removal of the tumour as reported by the surgeon and pathologist. In case of any doubt the lack of residual tumour must be confirmed with imaging studies performed	Within 2 weeks after surgery.
Secondary	Complete remission	Lack of evidence of residual disease and normal (for age) alpha-foetal protein (AFP). To establish a complete remission all of the following requirements must be fulfilled: No evidence of tumour intra-abdominally: negative abdominal (including hepatic) ultrasound or CT scan or Magnetic resonance imaging; No evidence of metastases: clear chest X-ray (PA and lateral) for non-metastatic patients. (Normal lung CT scan for patients with lung metastasis at diagnosis, who are high-risk by definition and not treated according to SIOPEL 6).; Serum AFP level either normal or compatible with age for at least 4 weeks after normalisation.	End of trial treatment
Secondary	Event-free survival (EFS)	Calculated from the time of randomisation to the first of the following events: progression, relapse, secondary primary malignancy or death.	Until first event or up to 5 years
Secondary	Overall survival (OS)	Calculated from the time of randomisation to death.	Until event or up to 5 years
Secondary	Toxicity as graded by CTCAE v 3.0	Adverse drug reactions are defined as adverse events, which are possibly, probably or definitely related to the trial treatment. They will be assessed according to NCI CTCAE v 3.0.	30 days post treatment
Secondary	Long-term renal clearance	By clearance method either EDTA, iohexol or inulin.	Until event or up to 5 years
Secondary	Feasibility of central audiology review	The feasibility of central review	End of trial treatment or at an age of 3.5 years, whichever is later